A new modification of the Friedlaender synthesis. A simple route to 2-aminoquinoline-3-carboxylic acid and its derivatives

Article abstract of DOI:10.1007/s11172-008-0065-0

A new version of the Friedlaender synthesis of 2-aminoquinoline-3- carboxylic acid and its derivatives from stable 2-tosylaminobenzaldehyde or its morpholinal was proposed.

Full text of DOI:10.1007/s11172-008-0065-0

Russian Chemical Bulletin, International Edition, Vol. 57, No. 2, pp. 418—421, February, 2008
418
A new modification of the Friedländer synthesis.
A simple route to 2ꢀaminoquinolineꢀ3ꢀcarboxylic acid and its derivatives
L. Yu. Ukhin and E. G. Belov
Research Institute of Physical and Organic Chemistry, Southern Federal University,
194/2 prosp. Stachki, 344090 RostovꢀonꢀDon, Russian Federation.
Fax: +7 (863) 243 4776. Eꢀmail: may@ipoc.rsu.ru
A new version of the Friedländer synthesis of 2ꢀaminoquinolineꢀ3ꢀcarboxylic acid and its
derivatives from stable 2ꢀtosylaminobenzaldehyde or its morpholinal was proposed.
Key words: Friedländer synthesis, 2ꢀaminoquinolineꢀ3ꢀcarboxylic acid, 2ꢀaminoquinolineꢀ
3ꢀcarboxylic acid derivatives, 2ꢀtosylaminobenzaldehyde, 2ꢀtosylaminobenzaldehyde morpholinal,
cyanoacetic acid, cyanoacetic acid derivatives.
A common route to substituted quinolines involves
Under the same conditions, morpholinal 1 analogously
reacts with ethyl cyanoacetate (2b), malononitrile (2c),
and cyanoacetamide (2d) to give ethyl 2ꢀaminoquinolineꢀ
3ꢀcarboxylate (6b), 2ꢀaminoꢀ3ꢀcyanoquinoline (6c), and
2ꢀaminoquinolineꢀ3ꢀcarboxamide (6d), respectively.
The synthesis can be carried out in one step, starting
from 2ꢀtosylaminobenzaldehyde and morpholine or pipꢀ
eridine used in stoichiometric amounts: the correspondꢀ
ing aminal is formed in situ. A plausible mechanism of the
reaction is shown in Scheme 1.
the Friedländer synthesis1,2 via condensation of oꢀamino
carbonyl compounds with compounds containing a
—CH2CO— fragment.
It is known that the cyano group can participate in
cyclization with the amino group of 2ꢀarylꢀoꢀaminoꢀ
cinnamonitriles into 2ꢀaminoquinoline derivatives.3
Great attention has been given to the synthesis of
3ꢀsubstituted 2ꢀaminoquinolines and the study of its
reactions (e.g., the synthesis of 2ꢀaminoquinolineꢀ
3ꢀcarboxamide from 2ꢀaminobenzaldehyde and cyanoaceꢀ
tic acid derivatives).4,5 Two routes to 2ꢀaminoquinolineꢀ
3ꢀcarboxylic acid have been proposed. According to both,
the synthesis is carried out in a closed steel bomb at
180 °C by hydrolysis of 2ꢀaminoquinolineꢀ3ꢀcarboxamide
(4 h) or 2,4ꢀdihydroxypyrimido[4,5ꢀb]quinoline (12.5 h)
in the presence of conc. NH4OH.
Nꢀ(pꢀTolylsulfonyl)morpholine (7) was isolated and
characterized and so was Nꢀ(pꢀtolylsulfonyl)piperidine (8)
obtained by the oneꢀstep synthesis with piperidine.
Compounds 7 and 8 contrast with their carbocyclic
analogs in reactivity. We failed to obtain 2ꢀaminoquinoꢀ
lineꢀ3ꢀcarbohydrazide by heating the corresponding ester
6b with hydrazine hydrate in boiling PriOH: only the startꢀ
ing ester was recovered. An analogous behavior of alkyl
2ꢀaminothiopheneꢀ3ꢀcarboxylates has been reported
earlier;10 the corresponding hydrazides have been syntheꢀ
sized in an indirect way.11 We obtained 2ꢀaminoquinolineꢀ
3ꢀcarbohydrazide (9) in moderate yield by shortꢀtime
reflux of ester 6b or amide 6d with hydrazine hydrate
(Scheme 2). Reflux of 2ꢀaminoquinolineꢀ3ꢀcarboxylic
acid with acetic anhydride resulted, as with anthranilic
acids,12 in rapid closure of an oxazine ring, giving
2ꢀmethylꢀ3,1ꢀoxazino[4,5ꢀb]quinolinꢀ4ꢀone (10). Its anaꢀ
log, 5ꢀmethylꢀ2ꢀphenylꢀ3,1ꢀoxazino[4,5ꢀb]quinolinꢀ4ꢀone,
have been recently obtained in a mixture with 5ꢀmethylꢀ
2ꢀphenylꢀ2ꢀdeoxoꢀ5ꢀdeazaalloxazine by refluxing
2ꢀaminoꢀ4ꢀmethylquinolineꢀ3ꢀcarbonitrile with benzoyl
chloride in pyridine for 6 h.13
We found no literature references to the direct synꢀ
thesis of 2ꢀaminoquinolineꢀ3ꢀcarboxylic acid from
2ꢀaminobenzaldehyde and cyanoacetic acid.
A substantial drawback of 2ꢀaminobenzaldehyde is its
low stability. Stable 2ꢀaminobenzaldehyde azomethines
are employed in the modified Friedländer synthesis.6
Here we proposed an alternative way of stabilizing the
starting compounds, viz., through the use of 2ꢀtosylaminoꢀ
benzaldehyde morpholinal7 stable under normal condiꢀ
tions. This compound can be easily prepared in high yield
from stable 2ꢀtosylaminobenzaldehyde (the synthesis
of the latter allows one to avoid the formation of
2ꢀaminobenzaldehyde8,9).
We found that reflux of morpholinal 1 with cyanoꢀ
acetic acid 2a in acetonitrile for 30 min gives 2ꢀaminoꢀ
quinolineꢀ3ꢀcarboxylic acid 6a in 85% yield (Scheme 1).
Being virtually insoluble in boiling MeCN, the product
can be isolated by mere filtration.
Reactions of N´ꢀmesylanthranilohydrazide14 with
aldehydes and cyclic ketones give 1,2,3,4ꢀtetrahydroꢀ
quinazolinꢀ4ꢀones and those with formic acid yield
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 408—411, February, 2008.
1066ꢀ5285/08/5702ꢀ0418 © 2008 Springer Science+Business Media, Inc.

2ꢀAminoquinolineꢀ3ꢀcarboxylic acid
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 2, February, 2008
419
Scheme 1
R = COOH (a), COOEt (b), CN (c), CONH2 (d); X = O (7), CH2 (8)
3ꢀmethylsulfonylaminoꢀ3,4ꢀdihydroquinazolinꢀ4ꢀone.
Starting from morpholinal 1 and cyanoacetic acid methylꢀ
sulfonylhydrazide (11), we obtained N´ꢀmethylsulfonylꢀ
2ꢀaminoquinolineꢀ3ꢀcarbohydrazide (12), a quinoline
analog of N´ꢀmesylanthranilohydrazide (Scheme 3). Howꢀ
ever, hydrazide 12 was inert in reactions characteristic of
anthranilic acid derivatives. After reflux in HCOOH for
1 h, this hydrazide was precipitated from the reaction
mixture with ether almost completely. Its reactions with
aldehydes and cyclohexanone resulted only in resinification.
Heating of hydrazide 12 in an excess of triethyl
orthoformate (13) afforded, probably through imino ether
14, the expected 3ꢀmethylsulfonylaminoꢀ4(3H)ꢀoxopyrimidoꢀ
[4,5ꢀb]quinoline (15) (Scheme 4).
Scheme 4
Scheme 2
Experimental
Scheme 3
IR spectra were recorded on a Specord IRꢀ75 instrument in
Nujol. 1H NMR spectra were recorded on a Varian UNITYꢀ300
spectrometer. Mass spectra were recorded on a Finnigan MAT
INCOS 50 GCꢀMS spectrometer (direct inlet probe). The specꢀ
troscopic characteristics of the compounds obtained are given in
Table 1.
2ꢀAminoquinolineꢀ3ꢀcarboxylic acid (6a). A. 2ꢀTosylaminoꢀ
benzaldehyde morpholinal (1) (0.43 g, 1 mmol) was dissolved
under heating in MeCN (5 mL) and refluxed with cyanoacetic
acid (2a) (0.12 g, 0.15 mmol) for 30 min. On cooling to ambient

420
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 2, February, 2008
Ukhin et al.
Table 1. Spectroscopic characteristics of the compounds obtained
Comꢀ
pound
[M]+
188
IR, ν/cm–1
(Nujol)
Solvent
1H NMR
δ (J/Hz)
6а
6b
6c
6d
7
3230, 1940 (NH2, NH3+);
1700 (CO); 1620 (arom.)
DMSOꢀd6
7.22 (m, 1 Н, СH arom.); 7.48 (br.d, 1 Н, СH arom.);
7.61 (m, 1 Н, СH arom.); 7.83 (d, 1 Н, СH arom., J = 7.9);
8.74 (s, 1 Н, С(4)Н)
216
3420, 3260, 3140 (NH2);
1687 (СО); 1627, 1614,
1560, 1500, 1475 (arom.)
3387, 3315,3140 (NH2);
2220 (CN); 1647, 1614,
1594, 1554 (arom.)
3393, 3180 (br.) (NH);
1647, 1627 (CO); 1607,
1600, 1560, 1487 (arom.)
1594, 1447 (arom.), 1340,
1167 (SO2)
CDCl3
1.43 (t, 3 Н, Me, J = 7.1); 4.40 (q, 2 H, CH2, J = 7.1);
6.23 (br.s, 2 Н, NH2); 7.10—7.30 (m, 1 Н, СН arom.);
7.50—7.70 (m, 3 Н, СН arom.); 8.69 (s, 1 Н, С(4)Н)
6.64 (s, 2 H, NH2); 7.19 (m, 1 Н, СН arom.);
7.49 (d, 1 Н, СН arom., J = 8.4); 7.56 (m, 1 Н, СН arom.);
7.65 (d, 1 Н, СН arom., J = 8.1); 8.47 (s, 1 Н, С(4)Н)
7.10 (s, 2 H, NH2), 7.13 (m, 1 H, CH arom.);
7.36 (s, 1 Н, CONH2); 7.47 (m, 2 Н, СН arom., J = 7.9);
8.10 (s, 1 Н, CONH2); 8.45 (s, 1 H, C(4)H)
DMSOꢀd6
DMSOꢀd6
CDCl3
2.44 (s, 3 H, Me); 2.98 (t, 4 Н, СН2N, J = 4.7);
3.74 (t, 4 Н, СН2O, J = 4.7); 7.35 (d, 2 Н, СН arom.,
J = 8.2); 7.64 (d, 2 Н, СН arom., J = 8.2)
8
1594, 1487, 1450 (arom.);
1327, 1167 (SO2)
CDCl3
1.38 (m, 2 Н, С(4´)Н2); 1.60 (m, 4 Н, С(3´)H2, C(5´)H2);
2.41 (s, 3 H, Me); 2.94 (t, 4 Н, С(2´)H2, C(6´)H2, J = 5.5);
7.29 (d, 2 Н, С(3)Н, С(5)Н, J = 8.2); 7.61 (d, 2 Н, C(2)H,
C(6)H, J = 8.2)
9
202
3430—3100: 3365, 3290,
3180 (NH); 1647,
DMSOꢀd6
4.37 (br.s, 2 Н, NNH2); 6.92 (s, 2 H, C(2)NH2);
7.18 (m, 1 H, CH arom.); 7.47 (m, 2 H, СH arom.);
8.31 (s, 1 H, C(4)H); 9.91 (s, 1 H, NH)
1620 (CO); 1567, 1527,
1514, 1487 (arom.)
1760 (СО); 1650 (C=N);
1607, 1594, 1567, 1614,
1594, 1554 (arom.)
3340, 3300, 3100 (NH);
2260 (CN); 1714,1687,
1667 (CO); 1327,
10
11
212
177
CDCl3
2.59 (s, 3 Н, Me); 7.69 (m, 1 Н, СН arom.); 7.93 (m, 1 Н,
СН arom.); 8.03 (br.d, 1 Н, СН arom.); 8.21 (d, 1 Н,
СН arom., J = 7.9); 9.15 (s, 1 Н, С(5)Н)
2.90 (s, 3 H, Me); 3.61 (s, 2 H, CH2); 9.56 (d, 1 Н, NH,
J = 2.7); 10.44 (d, 1 Н, NH, J = 2.7)
DMSOꢀd6
1140 (SO2)
12
15
280
290
3420, 3220, 3113 (NH);
1660 (CO); 1634, 1614,
1567, 1514, 1493 (arom.),
1340, 1140 (SO2)
DMSOꢀd6
DMSOꢀd6
3.00 (s, 3 H, Me); 6.94 (s, 2 H, NH2); 7.17 (m, 1 Н,
СН arom.); 7.40—7.60 (m, 2 Н, СН arom.); 7.65 (d, 1 Н,
СН arom., J = 7.9); 8.50 (s, 1 H, C4)H); 9.57 (s, 1 H, NH);
10.88 (s, 1 H, NH)
3.20 (s, 3 H, Me); 7.71 (m, 1 Н, СН arom.); 7.98 (m, 1 Н,
СН arom.); 8.20 (d, 1 Н, СН arom., J = 8.5); 8.28 (d, 1 Н,
СН arom., J = 8.2); 8.49 (s, 1 H, C(5)H); 9.39 (s, 1 H,
C(2)H); 11.39 (s, 1 H, NH)
3214, 3200 (NH);
1694 (CO); 1614, 1594,
1500 (arom.); 1354,
1154 (SO2)
temperature, the precipitate that formed was filtered off,
washed with acetonitrile, and dried to give colorless crystals,
m.p. 327—328 °C (cf. Ref. 4: m.p. 324—325 °C). The yield was
0.162 g (86%).
B. 2ꢀTosylaminobenzaldehyde8 (2.0 g, 7.3 mmol) was disꢀ
solved in a mixture of MeCN (20 mL) and piperidine (1.2 mL,
12 mmol). The resulting solution was refluxed with cyanoacetic
acid (1 g, 12 mmol) for 1 h and filtered hot. The precipitate was
washed with MeCN and ether and dried to give colorless crysꢀ
tals, m.p. 327—328 °C. The yield was 1.1 g (80 %).
Nꢀ(pꢀTolylsulfonyl)morpholine (7). The filtrate obtained in
the synthesis of acid 6a (method A) was diluted with water. The
precipitate that formed was filtered off and recrystallized from
isooctane to give colorless crystals, m.p. 147—150 °C (cf. Ref.
15: m.p. 147 °C). The yield was 0.086 g (36%). Found (%): C,
54.69; H, 6.47; N, 5.74. C11H15NO3S. Calculated (%): C, 4.75;
H, 6.27; N, 5.80.
Nꢀ(pꢀTolylsulfonyl)piperidine (8) was isolated from the filtrate
obtained in the synthesis of acid 6a (method B) as described for comꢀ
pound 7. The yield was 0.8 g (46%), colorless crystals, m.p. 92—94 °C
(cf. Ref. 16: m.p. 95—96 °C). Found (%): C, 60.00; H, 7.38; N,
5.96. C12H17NO2S. Calculated (%): C, 60.22; H, 7.16; N, 5.85.
Ethyl 2ꢀaminoquinolineꢀ3ꢀcarboxylate (6b). Ethyl cyanoꢀ
acetate (0.32 g, 3 mmol) was added to a solution of morpholinal
1 (0.86 g, 2 mmol) in acetonitrile (5 mL). The mixture was
heated to boiling, refluxed for 30 min, and filtered hot through a
filter funnel with a dense sintered disk to remove slight mud. On
cooling to ambient temperature by triturating with a rod, the
mixture was kept on ice for 1 h. The precipitate that formed was
filtered off, washed with cold acetonitrile and light petroleum,
and dried to give light yellow crystals, m.p. 135—137 °C (cf. Ref. 16:
m.p. 135 °C). The yield was 0.205 g (47%). Found (%): C,
66.43; H, 5.74; N, 12.80. C12H12N2O2. Calculated (%): C, 66.65;
H, 5.59; N, 12.95.

2ꢀAminoquinolineꢀ3ꢀcarboxylic acid
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 2, February, 2008
421
2ꢀAminoꢀ3ꢀcyanoquinoline (6c). Morpholinal 1 (0.86 g, 2 mmol)
was heated in MeCN (5 mL) to boiling, refluxed with
malononitrile (0.18 g, 2.7 mmol) for 30 min, and cooled to
ambient temperature while triturating with a rod. After 3 h, the
precipitate that formed was filtered off, washed with cold MeCN
and light petroleum, and dried to give pale yellow crystals,
m.p. 235—236 °C (cf. Ref. 4: m.p. 228.5—230 °C). The yield was
0.286 g (92%).
2ꢀAminoquinolineꢀ3ꢀcarboxamide (6d). Morpholinal 1 (0.86 g,
2 mmol) and cyanoacetamide 2d (0.252 g, 3 mmol) (see Ref. 17)
were refluxed in MeCN (5 mL) for 30 min and cooled on ice.
The precipitate that formed was filtered off and recrystallized
from water to give yellow crystals, m.p. 240 °C (cf. Ref. 4:
m.p. 240—242 °C). The yield was 0.264 g (70%).
2ꢀAminoquinolineꢀ3ꢀcarbohydrazide (9). A. Ester 6b (0.44 g,
2 mmol) was refluxed in hydrazine hydrate (2.0 mL) for 10 min.
Then water (5 mL) was added and the mixture was cooled on
ice. The precipitate that formed was filtered off, washed with
cold PriOH, dried, and recrystallized from PriOH to give light
yellow crystals, m.p. 188—189 °C. The yield was 0.236 g (58%).
Found (%): C, 59.08; H, 5.33; N, 27.42. C10H10N4O. Calcuꢀ
lated (%): C, 59.39; H, 4.98; N, 27.70.
3ꢀMethylsulfonylaminoꢀ4(3H)ꢀoxopyrimido[4,5ꢀb]quinoline
(15). Hydrazide 12 (0.118 g, 0.42 mmol) was refluxed in triethyl
orthoformate (2.0 mL) for 30 min. The starting compound did
not dissolve completely, giving an insoluble reaction product.
On cooling with ice, the precipitate that formed was filtered
off, washed with EtOH, and dried to give colorless crystals,
m.p. 284—290 °C (decomp.). The yield was 0.06 g (49%). Found
(%): C, 50.03; H, 3.76; N, 19.45; S, 11.46. C12H10N4O3S. Calꢀ
culated (%): C, 49.65; H, 3.47; N, 19.30; S, 11.04.
References
1. P. Friedländer, Ber., 1882, 15, 2572.
2. Heterocyclic Compounds, Ed. R. C. Elderfield, John Wiley
and Sons, Inc., Ltd, New York; Chapman and Hall, London,
V. 4, 1952.
3. R. Pschorr, Ber., 1898, 31, 1289.
4. E. C. Taylor, N. W. Kalenda, J. Am. Chem. Soc., 1953, 75,
1755.
5. E. C. Taylor, N. W. Kalenda, J. Am. Chem. Soc., 1956, 78,
5108.
6. W. Borshe, W. Ried, Liebigs Ann., 1943, 554, 269.
7. L. Yu. Ukhin, V. N. Komissarov, Zh. I. Orlova, G. S.
Borodkin, S. V. Lindeman, V. N. Khrustalev, Yu. T. Struchkov,
Izv. Akad. Nauk, Ser. Khim., 1995, 2236 [Russ. Chem. Bull.,
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8. B. M. Bolotin, D. A. Drabkina, V. G. Brudz´, Metody
polucheniya khimreaktivov i preparatov [Methods for the
Preparartion of Reagents and Chemicals], IREA, Moscow,
1964, issue 9, p. 12 (in Russian).
9. N. I. Chernova, Yu. S. Ryabokobylko, V. G. Brudz´, B. M.
Bolotin, Zh. Org. Khim., 1971, 7, 1670 [J. Org. Chem., USSR,
1971, 7 (Eng. Transl.)].
10. K. Gewald, Khim. Geterotsikl. Soedin., 1976, 1299 [Chem.
Heterocycl. Compd., 1976, 12 (Engl. Transl.)].
11. R. Gompper, E. Kutter, Angew. Chem., Int. Ed. Engl., 1962,
74, 285.
12. M. T. Bogert, H. A. Seil, J. Am. Chem. Soc., 1905, 27, 1305.
13. Abd ElꢀWareth, A. O. Sarhan, Z. A. Hozien, H. A. H. ElꢀSherif,
Bioorg. Med. Chem., 2001, 9, 2993.
14. L. Yu. Ukhin, L. G. Kuz´mina, Izv. Akad. Nauk, Ser. Khim.,
2006, 1183 [Russ. Chem. Bull., Int. Ed., 2006, 55, 1229].
15. Beilsteins Handbuch der organischen Chemie, 1937, 28, 8 (in
German).
16. Dictionary of Organic Compounds, Eds I. Heilbron, H. M.
Bunbury, London, 1946.
17. Organikum, Organischꢀchemisches Grundpraktikum 15, Überꢀ
arbeitete Auflage, VEB Deutscher Verlag der Wissenschaften,
Berlin, 1976 (in German).
B. Compound 9 was obtained from amide 6d (0.38 g, 2 mmol)
under the conditions described above. The yield was 0.124 g
(30%), light yellow crystals, m.p. 188—189 °C.
2ꢀMethylꢀ3,1ꢀoxazino[4,5ꢀb]quinolinꢀ4(4H)ꢀone (10). Acid
6a (0.5 g, 2.6 mmol) was refluxed in Ac2O (5 mL) to complete
homogenization (~15 min). On cooling, ether (3 mL) was added
and the mixture was cooled on ice. The precipitate that formed
was filtered off, washed with ether and light petroleum, and dried.
The yield was 0.44 g (77%), pinkish crystals, m.p. 216—218 °C.
Found (%): C, 68.13; H, 4.07; N, 12.86. C12H8N2O2. Calcuꢀ
lated (%): C, 67.92; H, 3.80; N, 13.20.
Cyanoacetic acid methylsulfonylhydrazide (11). Methaneꢀ
sulfonyl chloride (5 mL, 65 mmol) was added to cyanoacetoꢀ
hydrazide (4.0 g, 40 mmol) (prepared according to a standard
procedure18 from ethyl cyanoacetate and hydrazine hydrate in
EtOH at 60—70 °C) in MeCN (10 mL). The mixture was heated
with pyridine (4.0 mL) to boiling. On cooling to ambient temꢀ
perature, the mixture was diluted with cold water (75 mL) and
kept in the presence of a nucleator for 1.5 h. The precipitate that
formed was filtered off, washed with water, dried a little on the
filter, and recrystallized from PriOH (50 mL). The yield was 3.2 g
(44%), colorless crystals, m.p. 144 °C. Found (%): C, 27.35; H,
4.23; N, 23.50; S, 17.90. C4H7N3O3S. Calculated (%): C, 27.12;
H, 3.98; N, 23.72; S, 18.09.
NґꢀMethylsulfonylꢀ2ꢀaminoquinolineꢀ3ꢀcarbohydrazide (12).
Morpholinal 1 (0.86 g, 2 mmol) and hydrazide 11 (0.4 g, 2.2 mmol)
were refluxed in MeCN (10 mL) for 30 min. Then the mixture
was cooled while triturating with a rod and kept on ice for 1 h.
The precipitate that formed was filtered off, washed with MeCN
and ether, and dried. The yield was 0.25 g (45%), colorless
crystals, m.p. 252—255 °C. Found (%): C, 46.84; H, 4.58;
N, 20.17; S, 11.23. C11H12N4O3S. Calculated (%): C, 47.14;
H, 4.32; N, 19.99; S, 11.44.
18. WeygandꢀHilgetag organischꢀchemische Experimentierꢀ
kunst, Neubearbeitete Auflage, Johann Ambrosius Barth
Verlag, Leipzig, 3, 1964 (in German).
Received June 26, 2007;
in revised form November 19, 2007